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Vaccine Tales Wag Dogs, Mice, and Men and Women and Children

Pick a tropical disease, any one of at least a dozen, and chances are that someone is developing a vaccine or some other immune system-modulating scheme to prevent and perhaps also to help treat it. The high prevalence of some of these diseases, their overall economic impact wherever they are endemic, and the undeniably high costs that stand in the way of treating them with proprietary drugs make vaccine development an essential strategy for combating them. But what a wild and varied strategy vaccine development turns out to be, according to several investigators who described their efforts along these lines during the 10th annual meeting of the International Centers for Tropical Disease Research Network, a program of the National Institute of Allergy and Infectious Diseases (NIAID), on 7-9 May in Bethesda, Md.

"There are no rules for going about these projects,"says Steven Reed, chief scientific officer of Corixa Corporation, a biotechnology company based in Seattle, Wash. He and his colleagues are developing several vaccines for diseases that are prevalent in the tropics, and they are collaborating with large international corporations, seeking federal grants, and lately finding support also from the William and Melinda Gates Family Foundation. "A recent influx from the Gates Foundation is really helping with neglected vaccines," he says. That help came following roadblocks Corixa encountered in some of its collaborations with big companies, one of which let a promising vaccine sit idly because the corporation had slipped into a period of "merger paralysis."

Leishmaniasis, a group of diseases caused by infections with protozoa of the genus Leishmania, is the target of a Corixa vaccine development program, according to Reed. To justify this effort to its investors, the company plans to develop, test, and market a canine-directed version of the vaccine for profit, he says, with additional plans to test a human-directed version in U.S. clinics and then move it, if successful, into developing countries. Biologically, dogs are a reservoir for the parasites but, economically, they may provide the best hopes of a profitable market.

Meanwhile, a prototype vaccine does well protecting mice, which represent no vaccine market but are biologically valuable because they are at least partly susceptible to the parasite. Some 60 antigens from the parasite were tested individually in mice, and 3 that did the best job of protecting the animals against infections were chosen for further development, Reed says. Gene sequences encoding the active parts of those three antigens now are combined into a single entity that does an even better job of protecting mice and, when reformulated with adjuvant lipids, also works well in rhesus monkeys and can cure parasite-infected dogs that fail to respond to drug treatment, he says. There are plans for testing the vaccine in dogs in Brazil and Italy, and phase I safety testing in humans could begin later this year.

The complex duality of host immune responses is a major reason behind the difficulties experienced in developing vaccines to protect against parasites, says Alan Sher of NIAID. In the mid-1980s, researchers discovered that the immune system responds along two divergent pathways, known as Th-1 and Th-2, to various pathogens. And since that time, molecular descriptions of these two interacting pathways have grown ever more intricate, replete with dozens of acting and counteracting cytokines that are situated along networks and help to determine whether any particular parasite will trigger a protective or damaging response or will reside pretty much unhindered by the immune system—in effect, immune to immunity.

When recombinant versions of potent cytokines first became available, many investigators seized on them as potential therapeutic agents and immune system modulators in their own right, according to Sher. But administering them safely to patients often proves to be a formidable, perhaps insurmountable challenge--they are expensive and, sometimes, deadly, he points out, referring to a clinical trial in which interleukin-12 (IL-12) toxicity led to several deaths.

"Where the field is going . . . is to manipulate cytokine networks to alter effector functions, with cytokines or antagonists used as adjuncts to chemotherapy . . . and as vaccine adjuvants" Sher says. Calling IL-12 and interleukin-10 (IL-10) the "yin and yang"of cytokines, with IL-10 being the "surge protector," he says that reshaping the balance of this duo may be the key to protecting humans against a wide assortment of pathogens and parasites. " The aim is to bias the immune response."

For instance, Sher and his colleagues are studying the immune system of mice to learn what happens during infections caused by Toxoplasma gondii, a parasite that in immunocompromised humans, particularly AIDS patients, can cause severe cerebral infections but otherwise does little harm. When mice are infected by this parasite, IL-12 controls the parasite, meaning the animals show no symptoms of disease but remain infected. However, parasite-infected animals that are genetically unable to produce IL-10 quickly go into shock and die—"not of the infection, but from tissue damage and overproduction of cytokines," he says.

One way to control these potentially catastrophic immune system responses involves tinkering with antigen-presenting dendritic cells, according to Sher. "The new direction is to manipulate the cells that produce cytokines rather than the cytokines themselves . . . to prevent immunopathology," he says. "The opposite scenario is to use dendritic cells to immunize the animals." In either case, the key is "keeping the balance. Although these strategies are tricky to translate into something clinically useful, some of them do work."

Jeffrey L. Fox
Jeffrey L. Fox is the ASM News Current Topics and Features Editor.